Infection in Pregnancy

Bacteria of the Female Genital Tract

• Upper tract – sterile unless infected by ascending bacteria or hematogenous spread
• Lower tract – colonized with a mixture of commensal and pathogenic flora, which are similar to skin and fecal flora
• Lactobacilli species predominate Þ produce and thrive in acid environment (pH 3.8-4.2)
• changes in bacterial environment can affect pregnancy; Bacterial vaginalis (BV) Þ associated with preterm delivery

Antibiotics Contraindicated During Pregnancy

• Chloramphenicol – Grey Baby Syndrome; Tetracyclines – bone effects, dental stains; Quinolones – animal arthropathy/stunting; Sulfonamides – risk of neonatal jaundice (unsafe at term, but safe otherwise); Nitrofurantoin – G6PD deficient anemia; Aminoglycosides – otoxtocity Þ used in neonates for gram negative bacteria; no alternatives

Infections During Pregnancy

• Most infections are no more severe during pregnancy than in the absence of pregnany; none are less severe
• some are more severe (reason unknown): polio, influenza, varicella, amebioasis, listeria, malaria, coccidiomycosis
• Maternal Changes – minimal changes in immunoglobulins; no clear immune dysfunction
• Ý risk of upper respiratory tract infections(URI) and urinary tract infections(UTI), tendency toward earlier systemic invasion, and Ý risk for sepsis and life-threatening pulmonary fluid shift and adult respiratory distress syndrome (ARDS)
• Ý risk of URI: possibly due to ß plasma oncotic pressure, Ý O₂ demands, ß difference in alveolar closing pressures
• Ý risk of enteric infections: possibly due to altered gastric acidity and motility
• Teratogenic Infections–acronym "TORCH" Þ Toxoplasmosis, Other (Syphilis), Rubella Cytomegalovirus, and Herpes virus
• also trypanosomiasis, coxsackie virus, common colds, varicella, parvovirus B19, Venezuelan Equine Encephalitis (VEE)
• Toxoplasmosis – protozoan with tachyzoite, tissue cyst and oocyst phases: oocyst is infectious form
• acquired from undercooked meat and aerosolized cat feces Þ "Kitty Litter Disease"
• Maternal Symptoms – often asymptomatic; adenopathy malaise; only primary infection is dangerous to fetus unless immunosuppression causes recurrent attacks Þ fetal lesions and life-threatening maternal disease
• Neonatal Symptoms – CNS calcification, hydrocephaly, hepatic/splenic lesions, retinitis
• Diagnosis – history and serologic investigations, Ig assays and PCR of amniotic fluid and fetal blood
• Treatment – pyrimethamine/sulfadoxine or spiromycin; spiromycin does not cross the blood brain barrier
• Syphilis – STD caused by Treponema pallidum (9/100,000 women); can cause miscarriage
• Maternal Symptoms – same as non-pregnant pts.
• Neonatal Sympt.–bony lesions, jaundice, hepatosplenomegaly, mulberry molars, saber-shins, saddle nose, rhinorrhea
• Diagnosis – darkfield microscopy, serology of amniotic fluid and maternal or neonatal CSF
• Treatment–penicillin according to stage and HIV status (the only effective treatment–may have to desensitise if allergic)
• Rubella – virus, fetal exposure is dangerous through week 20; 50% affected if exposed during 1^st month, 10% after third
• Maternal Symptoms – minimal, rash, fever and mild adnopathy
• Neonatal Symptoms – cataracts, deafness, cardiac lesions, mental retardation, growth restriction
• Diagnosis – serologic testing
• Treatment – no effective treatment; vaccination program(RA 27/3 live virus); pregnancy interruption
• Cytomegalovirus – DNA herpesvirus; most prevalent cause for neonatal infections Þ 0.2 – 2 % of all live births; 10% result in clinical disease, 60% seroprevelance; spread by secretions, transfusion or vertically
• Maternal Symptoms – asymptomatic, mild mono-like illness with or without jaundice, primary infections most dangerous but reactivation accounts for almost ½ of infections; life threatening in immunosuppressed
• Neonatal Symptoms – hepatosplenomegaly, petechial skin lesions "blueberry muffin" chorioretinitis, hydrocephaly, hydrops, CNHS calcifications, growth restriction, deafness, neurobehavioral damage and death
• Diagnosis – serologic testing, antibody fixation testing, ultrasound PCR testing of amniotic fluid and fetal blood
• Treatment – no clearly effective treatments; future drugs Þ anti-retrovirals and hyperimmune gamma globulin

Sexually Transmitted Diseases – similar risk as other sexually active women

• Herpes Simplex Type 2–rarely teratogenic; vertical intrapartum transmission, primary infection in mother most dangerous
• Neonatal Symptoms – cataracts, microcephaly, growth restriction, encephalitis, pneumonia and skin lesions
• Treatment–cesarean if active lesions present; antiviral therapy for newborns and mothers; 25% of babies at risk infected
• Gonorrhea – dissemination more common if pregnant
• Congenial Symptoms – Neonatal opthalmitis can lead to blindness, sepsis, meningitis or death;
• Diagnosis – DNA probe and confirmatory culture
• Treatment – treat with 2^nd generation cephalosporins
• Chlamydia – late onset endometritis in mother and conjunctivitis and pneumonia in the newborn
• Diagnosis – DNA probe and confirmatory culture
• Treatment – Erythromycin; Tetracycline is contraindicated during pregnancy
• Human Papilloma Virus (HPV)–Ý lesion growth may be enhanced by estrogen, may obstruct canal and bleeding may be sufficient to require cesarean section; pediatric laryngeal papillomatosis may occur
• HIV – 4^th leading cause of death in women of childbearing age; maternal course is unaffected by pregnancy
• vertical transmission is 30% without maternal treatment; maternal antiviral therapy reduces vertical transmission
• Diagnosis – serologic testing, PCR for viral load
• Urinary Tract Infections
• more common in pregnancy because of hormonally mediated ureteral motility changes and mechanical obstruction
• usually caused by a single organism (gram negative enteric bacilli: E. coli, Klebsiella species, Group B Strep etc.)
• 2-7 % incidence of UTI; 25 progress to pyelonephritis if untreated
• Maternal Sympt.–can be asymptomatic, dysuria, frequent urination, fever, pain, urosepsis, associated with UTI and prematurity
• Treatment – oral antibiotics for lower tract infection; IV antibiotics for inpatients Þ emergency 

Pregnancy Specific Diseases

• Chorioamnionitis – 1-2% pregnancies; usu. polymicrobial, occasionally single strain (group B strep, gonococcus, listeria)
• Risk Factors – amniorrhexis, cerclage, labor duration, internal monitoring, exams, colonization by common pathogens
• Maternal Symptoms – fever, labor tachycardia, tenderness
• Neonatal Symptoms – cerebral palsy
• Diagnosis – WBC, CRP, amniocentesis and post facto placental culture and pathology
• Treatment – delivery and broad spectrum antibiotics
• Group B strep – gram positive bacterium with 10-20% colonization, frequent status change in women
• Maternal Symptoms – asymptomatic, urinary infections and endometritis
• Neonatal Symptoms – sepsis, pneumonia, late meningitis
• Diagnosis – culture with antenatal screening protocols; prophylactic treatment with intrapartum N penicillin
• Episiotomy Complications – uncommon; infections (0.05%), dehiscence (3-4%)
• polymicrobial pathogens with enteric anaerobes producing more sever cases
• Maternal Symptoms – fever, pain, purulence, incontinence, abscess
• Neonatal Effects – fistula formation, necrotizing fasciitis, sepsis
• Treatment – removal of sutures, debreedement, broad-spectrum antibiotics
• Peurperal Infections (Post Birth Infection) – polymicrobial, aerobes, rarely Group A streptococcus
• Symptoms – fever, uterine tenderness, foul lochia (discharge of tissue, blood and mucus following child birth)
• often self limiting; severe infections have sepsis, abscess, septic pelvic thrombophlebitis (SPT) and death
• Diagnosis – clinical, blood or cervical cultures
• Treatment - broad spectrum IV antibiotics; heparin for SPT

Antimicrobial revision

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Background
Divided by mode of action


1. inhibit cell wall synthesis – penicillins, cephalosporins, carbapenems, vancomycin, bacitracin, miconazole, ketoconazole, clotrimazole
2. increase permeability of cell membrane – polymyxin, nystatin, amphotericin B
3. reversibly inhibit protein synthesis by affecting ribosomes 30 S and 50 S (bacteriostatic) – chloramphenicol, tetracyclines, macrolides, clindamycin
4. alter protein synthesis via 30 S ribosomes (bactericidal) – aminoglycosides
5. inhibit nucleic acids – rifampin, quinolones
6. antimetabolites – trimethoprim, sulfonamides
7. nucleic acid analogs – act on viruses – acyclovir, zidovudine, ganciclovir

Scanning electron m icrographs illustrating external features of the rod-shaped bacterium E. coli. The top image above is from: http://www.uq.oz.au/nanoworld. The lower image above is from: http://www.slic2.wsu.edu:82/hurlbert/micro101/pages/Chap2.html#two_bact_groups


PENICILLINS (Beta Lactams)

General side-effects
1. Most important are hypersensitivity and anaphylaxis. Penicillins are the most common cause of drug allergy. All types, dosages and forms of administration can potentially cause allergic reactions. Cross-reactions among the penicillins and between them and the cephalosporins are not uncommon.
2. Local reactions to intramuscular injection may be seen. Oral administration may cause nausea and diarrhea.
3. Toxic effects are minimal.

Penicillin G and V
1. effective against
a. Gram-positive cocci (Streptococcus, Neisseria meningitidis, but not Enterococcus)
b. Trepenoma pallidum (syphilis)
c. Borrelia burgdorferi (Lyme disease)
d. some anaerobes (Clostridium, Corynebacterium diphtheriae, Actinomyces, Bacillus anthracis, Listeria) – not Bacteroides fragilis
2. Susceptible to penicillinase and so not effective against Staphylococcus aureus
3. Given orally (penicillin V less vulnerable to gastric acid) orparenterally; adding procaine or benzathine prolongs the effect of the penicillin. Best absorption is on an empty stomach.
4. Uses
a. To treat infections by above bacteria
b. As prophylaxis to prevent recurrent rheumatic fever, and in contacts of patients with syphilis, gonorrhea and streptococcal infections
c. Used as prophylaxis for infective endocarditis for susceptible people before dental or surgical procedures
5. Interactions – probenecid causes increased concentration
6. Jarisch-Herxheimer reaction
a. Seen in the majority of patients with secondary syphilis on receiving the first dose of penicillin
b. Flu-like symptoms – chills, fever, muscle aches, headache, joint pain – with enhanced color of the lesions of syphilis
c. Lasts for up to 48 hours and does not recur with later doses
d. May be due to antigens released by breakdown of the spirochetes
e. Not a reason to stop penicillin treatment; aspirin will help with symptoms

Penicillinase-resistant penicillins
1. Examples are methicillin, nafcillin, oxacillin, cloxacillin, and dicloxacillin
2. Effective against Gram-positive cocci (less so than penicillin V or G), including Staphylococcus aureus
3. MRSA = methicillin resistant S. aureus are treated by vancomycin.
4. Given orally (best absorption is on an empty stomach) andparenterally
5. Methicillin may cause interstitial nephritis.

Ampicillin, etc.
1. Examples are ampicillin, amoxicillin, bacampicillin
2. Effective also against some Gram-negative organisms – i.e. Hemophilus, E. coli, Proteus, also Salmonella and Listeria
3. Susceptible to b-lactamase – and so not effective for Staph. infections
4. Given orally (best is on an empty stomach) and parenterally
5. Ampicillin causes a rash in patients with infectious mononucleosis. Allopurinol will also increase chances of a rash with ampicillin.

Ampicillin and clavulanic acid
1. Clavulanic acid inactivates b-lactamase and so prevents breakdown of the antibiotic
2. Thus, the compound is effective against Staph. organisms.

Anti-Pseudomonas penicillins
1. Examples are carbenicillin and ticarcillin
2. Effective also against Pseudomonas, Enterobacter and Proteus
3. Susceptible to b-lactamase
4. Carbenicillin increases risk of heart failure, due to its ability to causehypernatremia and hypokalemia. It also interferes with aggregation of platelets. Ticarcillin has fewer side effects and so is preferred; it is given orally and parenterally.
5. A preparation of ticarcillin and clavulanic acid (for parenteral use) is more effective against Bacteroides, S. aureus and Gram-negative bacilli.

Broad-spectrum penicillins
1. Examples are mezlocillin and piperacillin
2. Effective also against Klebsiella and some other Gram-negative organisms
3. Susceptible to b-lactamase
4. Given only parenterally


CEPHALOSPORINS

General information
1. Most are given orally, intramuscularly or intravenously. Cephalothin is painful when injected intramuscularly and so should be used intravenously only. 
2. Need to reduce dose in cases of kidney dysfunction
3. Cefuroxime, moxalactam, cefotaxime, ceftriaxone, cefepime and ceftizoxime are found in therapeutic concentrations in the Cerebrospinal Fluid (CSF).
4. Cephalosporins cross the placenta.
5. Uses
a. As treatment for bacteria as given below
b. Prophylaxis for surgery
6. Side effects
a. Hypersensitivity reactions, as with penicillins; is cross-reactivity with penicillins
b. Diarrhea
7. Toxic effects – renal damage including acute tubular necrosis
8. Interactions - risk of nephrotoxicity increased with aminoglycosides

First generation
1. Examples are cephalothin, cefazolin, cephalexin and cefadroxil. The first two are given parenterally, the second two orally.
2. Effective against Gram-positive organisms (not including MRSA, S. epidermidis or Enterococcus) with slight activity against Gram-negative organisms (E. coli, Moraxella, Klebsiella, Proteus)

Second generation
1. Examples are cefoxitin, cefotetan, cefmanadole, cefuroxime, cefonicid and ceforanide that are given parenterally and cefaclor and loracarbef that can be given orally.
2. More effective against Gram-negative and less against Gram-positive than first generation cephalosporins; some are good against Bacteroides

Third generation
1. Examples are ceftazidime, cefoperazone, cefotaxime, ceftizoxime and ceftriaxone that are given parenterally, and cefpodoxime that can be given orally.
2. More effective against Gram-negative and less against Gram-positive than second generation cephalosporins, especially Enterobacter; some are good against Pseudomonas
3. Moxalactam can cause extensive hemorrhage.

Fourth generation
1. The only example available is cefepime, given parenterally.
2. Wider range than third generation and more stable against b-lactamase


CARBAPENEMS

Imipenem
1. A b-lactam antibiotic with a wide spectrum of activity; mode of action like penicillins and cephalosporins
2. Used when other antibiotics fail to eradicate bacteria
3. Given intravenously together with cilastin to prevent breakdown in the renal tubules

Aztreonam
1. Also wide spectrum, and not usually first line antibiotic
2. Activity mostly against Gram-negative organisms – especially Enterobacter and Pseudomonas


SULFONAMIDES AND TRIMETHOPRIM-SULFAMETHOXAZOLE (=CO-TRIMOXAZOLE)

1. Bacteriostatic against a wide range of Gram-positive and Gram-negative, but many organisms are resistant
2. Act by preventing synthesis of folic acid
3. Trimethoprim and sulfamethoxazole (a sulfonamide) together are synergistic in inhibiting folic acid and bacteria show less resistance.
4. Good oral absorption
5. Important for patient to be well hydrated and dose reduced (or avoided) in patient with renal insufficiency
6. Uses – used less these days, as bacteria become resistant
a. Sulfonamides are effective against Nocardia and Toxoplasma.
b. Can replace penicillin for prophylaxis in penicillin-sensitive patients
7. Side effects
a. Lack of appetite, nausea and vomiting
b. Can cause kernicterus in neonate if given to neonate or pregnant woman
c. Headache, depression, hallucinations
8. Toxic effects – hypersensitivity reactions, agranulocytosis, aplastic anemia
9. Contraindication – patients with G6PD deficiency – may cause acute hemolysis
10. Interactions – can increase effects of oral anticoagulants, sulfonylureas and hydantoin
11. Examples
a. Sulfisoxazole – used topically in the eye, with erythromycin for otitis media and for urinary tract infections.
b. Sulfasalazine is used in inflammatory bowel disease. Side-effects include nausea, fever, joint pain and rash. Toxic reactions include anemia and agranulocytosis.
c. Sulfacetamide is used topically in the eye.
d. Silver sulfadiazine is used on burns or decubitus (pressure) ulcers to prevent secondary bacterial or fungal infection
e. Trimethoprim-sulfamethoxazole is used in pediatric infections and in urinary tract infections and gastroenteritis. It is also effective against Pneumocystis carinii in AIDS patients. It is used for prophylaxis in neutropenic patients.

QUINOLONES

1. Examples are ciprofloxacin, ofloxacin and norfloxacin.
2. Act by inhibiting DNA gyrase
3. Well absorbed orally; also given parenterally
4. Effective against E. coli, Shigella, Salmonella, Enterobacter, Campylobacter and Neisseria. Ciprofloxacin is more effective against Pseudomonas, Enterococcus and Pneumococcus. Quinolones also effective against intracellular bacteria such as Chlamydia, Mycoplasma, Mycobacterium, Legionella and Brucella.
5. Uses - urinary tract infections, prostatitis, sexually-transmitted diseases, gastroenteritis
6. Side effects
a. Nausea, headache, dizziness, abdominal discomfort
b. Can increase risk of convulsions in patient with epilepsy
7. Interactions
a. Theophylline or non-steroidal anti-inflammatory drugs (NSAIDs) with a quinolone can cause hallucinations, delirium and even seizures.
b. Ciprofloxacin increases concentration of theophylline.
8. Contraindicated in children, pregnant or nursing women, and in epileptics.


DRUGS SPECIFIC FOR URINARY TRACT INFECTIONS

1. Concentration in urine with minimal systemic effects after oral administration
2. Examples are nalidixic acid, nitrofurantoin and methenamine.


AMINOGLYCOSIDES

General information
1. Examples are gentamicin, netilmicin, amikacin, streptomycin, tobramycin and neomycin.
2. Effective against aerobic Gram-negative organisms; amikacin has the widest spectrum
3. Not absorbed orally; given parenterally or topically
4. Uses
a. Gentamicin, tobramycin, amikacin and netilmicin are all used inpyelonephritis, hospital-acquired pneumonia, meningitis (by Gram-negative bacteria, given intrathecally), peritonitis, sepsis. 
b. Tobramycin is also used topically in the eye.
c. Streptomycin was the prototype; due to resistance, it is now used mostly in tuberculosis, tularemia and plague
d. Neomycin is used only topically or orally (to clean the intestines before abdominal surgery) because of its severe toxicities.
5. Toxic effects
a. Ototoxicity – act on both auditory and vestibular portions of cranial nerve VIII, damage is usually irreversible, main effect is hearing loss
b. Nephrotoxicity – usually mild and reversible; the main problem is decreased clearance increases risk of ototoxicity
c. Rare – neuromuscular blockade with apnea
d. Streptomycin may also cause damage to the optic nerve and peripheral neuritis
4. Interactions - Furosemide and ethacrynic acid are synergistic for hearing loss with aminoglycosides.


TETRACYCLINES

1. Broad spectrum – bacteriostatic against Gram-positive and Gram-negative organisms, including Rickettsia, Chlamydia, Mycoplasma pneumoniae, Brucella, Hemophilus ducreyi, Legionella, Helicobacter pylori, Trepenoma pallidum, Borrelia bungdorferi and Ureaplasma
2. Examples are tetracycline, doxycycline, minocycline and demeclocycline.
3. Usually given orally; can be parenterally or topically to the eye 
4. Uses – for treatment of infections by the above bacteria and also for the treatment of acne
5. Side effects
a. Damages intestinal flora and may cause fungal overgrowth, cause nausea, vomiting, diarrhea epigastric pain and abdominal discomfort (better if given with food); esophagitis and ulcers have been seen.
b. Severe thrombophlebitis may occur with intravenous use.
c. Demeclocycline and doxycycline may cause photosensitivity.
6. Toxic effects
a. Liver damage – especially in pregnant women
b. Renal damage – may worsen existing disease
c. Demeclocycline may cause nephrogenic diabetes insipidus (and so is used to treat the Syndrome of inappropriate Anti-diuretic Hormone (SIADH)).
d. Pigmentation of the teeth may occur in small children if tetracyclines are given to them or to their mothers during pregnancy.
e. Outdated tetracycline can cause a form of Fanconi’s syndrome.
7. Interactions – when given with dairy foods, antacids, iron compounds, sulcrafate or bismuth compounds, the metal will chelate and decrease the absorption of the antibiotic.
8. Contraindications – administration to children under 8 years old and pregnant or nursing women


CHLORAMPHENICOL

1. Effective against a wide range of bacteria; mostly bacteriostatic; may be bactericidal against Hemophilus, Neisseria and Pneumococcus
2. Given orally and parenterally
3. Due to the risk of aplastic anemia, chloramphenicol is reserved for cases where the infection is resistant to other less toxic antibiotics.
4. The “gray baby” syndrome is seen in neonates, mostly premature, who receive chloramphenicol. It is often fatal.
5. Interactions
a. Chloramphenicol increases half-lives of dicumarol, phenytoin, chlorpropamide and tolbutamide.
b. Its half-life is decreased by rifampin or phenobarbital.


MACROLIDES

1. Examples are erythromycin, azithromycin and clarithromycin. 
2. Usually bacteriostatic and effective against Gram-positive organisms, Chlamydia, Mycoplasma and Legionella; azithromycin and clarithromycin also effective against Hemophilus and Mycobacterium-avium-intracellulare.
3. Given orally in capsules or with enteric coating as gastric acid breaks the drug down; also given parenterally (intramuscular injection is painful). Give on an empty stomach.
4. Uses
a. for treatment of infections by the above organisms
b. for treatment of pertussis and prophylaxis of contacts
c. used for prophylaxis in penicillin-sensitive patients, particularly in pregnant women
5. Side effects
a. Gastro Intestinal Tract (GIT) effects can affect compliance – abdominal pain, nausea and vomiting
b. hypersensitivity
c. Cholestatic hepatitis – which is reversible after stopping the drug
6. Interactions – erythromycin increases effects of carbamazepine, steroids, cyclosporine, digoxin, theophylline, valproic acid, warfarin and more – via cytochrome P450


CLINDAMYCIN

1. Bacteriostatic against Gram-positive bacteria, anaerobes, Toxoplasma and Pneumocystis carinii
2. Given orally, topically and parenterally 
3. Uses
a. for the treatment of infections caused by the above bacteria
b. for the oral and topical treatment of acne
c. for the oral and topical treatment of bacterial vaginosis
4. Side effects
a. Major cause of pseudomembranous colitis
b. Also see skin rash and when given intravenously, thrombophlebitismay occur

VANCOMYCIN

1. Effective against Staph., Strep., Enterococcus, Corynebacterium and Clostridium
2. Given intravenously; orally for the treatment of pseudomembranous colitis
3. Uses
a. Treatment of pseudomembranous colitis
b. Treatment of infections caused by Methicillin-Resistant Staphylococcus aureus (MRSA)
c. Treatment of infections by above bacteria when other antibiotics fail
4. Side effects - hypersensitivity
5. Toxic effects
a. Ototoxicity – may be reversible
a. “Red man” syndrome – flushing, tachycardia and hypotension – occurs with too rapid intravenous infusion.
b. May be kidney damage if given with nephrotoxic drugs or to patient with renal disorder


BACITRACIN

1. Topical use only due to severe nephrotoxicity if given parenterally 
2. Effective against Gram-positive aerobes
3. Uses – eyes, skin


POLYMYXIN B

1. Topical use only due to severe nephrotoxicity if given parenterally 
2. Effective against Gram-negative bacteria, especially Pseudomonas
3. Uses – ears, eyes and skin



DRUGS FOR THE TREATMENT OF DISEASES CAUSED BY MYCOBACTERIUM


DRUGS FOR THE TREATMENT OF TUBERCULOSIS

Background
1. First line drugs are isoniazid, rifampin, ethambutol, streptomycin and pyrazinamide – they are the most efficient, have acceptable side effects and will treat most cases of tuberculosis in most people. Treatment is with 2 or 3 agents because use of one agent encourages resistance. There is minimal cross-resistance between the various agents.
2. Second line drugs are used in resistant cases or in patients with AIDS and include ofloxacin, ciprofloxacin, ethionamide, aminosalicylic acid, cycloserine, amikacin, kanamycin and capreomycin. They are only available for parenteral use. Due to ototoxicity and nephrotoxicity, these agents are only used if the first line drugs are not effective. Only one should be given with a first line agent, but not with streptomycin.
3. Different regimens are recommended. The basic regimen is isoniazid with rifampin and pyrazinamide for 2 months and then rifampin and isoniazid for another 4 months. Another possibility is isoniazid and rifampin for 9 months. The Centers for Disease Control (CDC) recommend four drugs together – isoniazid, rifampin, pyrazinamide and ethambutol or streptomycin.
4. The CDC regimen is recommended for those exposed to resistant strains and those with tuberculosis in sites other than the lungs or extensive disease in the lungs.
5. AIDS patients should receive at least the four-drug regimen, and in some cases a fifth or sixth drug may need to be added. Prophylactic treatment with isoniazid (ethambutol and pyrazinamide if exposed to resistant strains) is recommended to AIDS patients with positive Purified Protein Derivative (PPD) tests, anergy or at risk for tuberculosis.
6. In other patients, prophylaxis is recommended for those exposed totuberculosis, those with positive PPD but no clinical disease, those with history of active tuberculosis in the past who did not receive adequate treatment, and patients with anergy who come from a high-risk population. The recommended drug is isoniazid. Pregnant women and patients with active hepatic disease should receive prophylaxis at a later date.
7. The regimen of isoniazid, rifampin and ethambutol is considered to be safe for pregnant women.

Isoniazid
1. Drug of choice in tuberculosis
2. Mechanism of action is unknown.
3. Good oral and parenteral absorption; inactivation is via acetylation. Different populations have different proportions of “rapid” and “slow”acetylators, which influence how quickly the drug is inactivated.
4. Uses
a. Treatment of tuberculosis; usually two or three agents together
b. Alone for prophylaxis of tuberculosis
5. Side effects
a. Side effects include rash, fever, jaundice, hypersensitivity, arthritis,vasculitis, anemia, thrombocytopenia, eosinophilia andagranulocytosis.
b. Neurological side effects include peripheral neuritis, increased risk of convulsions in epileptics, euphoria, memory loss, psychosis, muscle twitches, dizziness, ataxia, paresthesias, stupor and encephalopathy.
c. To minimize neurological side effects, especially in patients with nutritional deficiencies (malnutrition, pregnancy, diabetes, chronic renal failure, elderly), pyridoxine (vitamin B6) is given together with the isoniazid.
d. Hepatotoxicity, which may be fatal, is not uncommon and the risk increases with increasing age. Need to watch very carefully for signs of hepatitis, besides jaundice that is a common side effect.
6. Toxic effects – coma, seizures, metabolic acidosis, hyperglycemia
7. Interactions – isoniazid increases concentrations of phenytoin, especially in slow acetylators. Adjustments as necessary should be made to the dose of phenytoin without changing the dose of isoniazid.
8. Contraindication – relative – hepatic disease

Rifampin
1. Effective against Gram-positive bacteria such as S. aureus, Hemophilus influenzae and Neisseria meningitidis and Gram-negative bacteria such as E. coli, Proteus, Klebsiella and Pseudomonas, as well as Mycobacterium, especially M. tuberculosis, M. kansasii and M. fortuitum
2. Acts by inhibiting RNA polymerase
3. Uses
a. in treatment of tuberculosis, together with isoniazid and others
b. for prophylaxis in people exposed to meningococcemia or H. influenzae type B meningitis
c. in cases of endocarditis or osteomyelitis resistant to other antibiotics
d. in leprosy
4. Given orally
5. Side effects
a. Colors body secretions orange
b. Rash, fever, nausea and vomiting, jaundice
c. Increased side effects are seen if rifampin is given infrequently or in high daily doses – a flu-like syndrome results that may develop into interstitial nephritis, acute tubular necrosis, hemolytic anemia and shock
d. Rifampin induces hepatic microsomal enzymes and so decreases the half-lives of many, many drugs. The most important of these aredigitoxin, quinidine, propanolol, oral anticoagulants, theophylline, barbiturates, oral contraceptives, halothane, methadone and sulfonylureas.
6. Toxic effects - Hepatotoxicity, especially in children, alcoholics, the elderly and patients with liver disease
7. Interactions
a. Is synergistic in vitro with streptomycin and isoniazid
b. Aminosalicylic acid may delay absorption of rifampin – best to give them 8-12 hours apart
8. Contraindications – best not to use in pregnancy or in patients with liver disease

Ethambutol
1. Mechanism of action is not known.
2. Oral absorption is good.
3. Uses – in treatment of tuberculosis together with other drugs
4. Side effects are minimal – blurry vision, rash, fever, headache,pruritus, arthralgia, dizziness, confusion, nausea and vomiting,hyperuricemia
5. Toxic effects - optic neuritis and red-green color blindness that are dose-dependent; should test visual acuity and color blindness before and during treatment with ethambutol
6. Contraindications – children under 5 years old

Streptomycin
1. Aminoglycoside antibiotic
2. Due to resistant bacteria and high toxicity, streptomycin is not often used today.
3. It is used together with two other drugs in disseminated tuberculosis or tuberculitic meningitis.
4. Side effects – rash, fever
5. Toxic effects – damage to cranial nerve VIII and the kidneys

Pyrazinamide
1. good oral absorption
2. uses – together with other drugs for the treatment of tuberculosis
3. side effects – hyperuricemia with clinical gout, arthralgia, nausea and vomiting, loss of appetitie, fever and painful urination
4. Toxic effects - liver disease is common and may be fatal; need to monitor liver function regularly
5. Contraindications – absolute – patient with liver disease




DRUGS FOR THE TREATMENT OF MYCOBACTERIUM AVIUM COMPLEX (MAC)


Background
1. MAC infection is common in AIDS patient where it is a disseminated disease. In patients without AIDS, it is usually restricted to the lungs.
2. Like tuberculosis, the use of one drug increases resistance and so the regiments are 2, 3 or 4 drugs.
3. The basic regimen is ethambutol with either clarithromycin or azithromycin.
4. Prophylaxis with rifabutin for life is recommended for AIDS patients with CD4 count under 100 cells/mm3.

Rifabutin
1. Derivative of rifampin
2. Used especially in AIDS patients
3. Given orally
4. Side effects – rash, nausea and vomiting, neutropenia, orange-colored body fluids
5. Toxic effects – uveitis, arthralgia
6. Like rifampin, induces hepatic microsomal enzymes and decreases concentrations of many drugs

Macrolides
1. Discussed in chapter on antibiotics
2. Examples are clarithromycin and azithromycin.
3. Used in combination with another agent (ethambutol, rifampin, rifabutin, ciprofloxacin, amikacin or clofazimine)
4. Toxic effects – tinnitus, dizziness and transient loss of hearing

Quinolones
1. Discussed in chapter on antibiotics
2. Used in AIDS patients – regimen is ciprofloxacin, clarithromycin, amikacin or rifampin, ethambutol, clofazimine and ciprofloxacin


DRUGS FOR THE TREATMENT OF LEPROSY

Sulfones
1. Most widely used is dapsone; sulfoxone is a derivative of dapsone
2. Dapsone is bacteriostatic for Mycobacterium leprae and is given orally.
3. Side effects – nausea, vomiting, lack of appetite, syndrome similar to infectious mononucleosis with possible mortality
4. Toxic effects – hemolysis, methemoglobinemia
5. A sulfone syndrome – similar to the Jarisch-Herxheimer reaction – may occur, with fever, jaundice, peeling skin, anemia and swollen glands.

Clofazimine
1. Used in MAC, but mainly in leprosy, together with other agents, for dapsone-resistant strains
2. Given orally
3. One side effect seen is red coloring of the skin


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